Clinical Research
Coronary Artery Disease
High-Density Lipoprotein Cholesterol, High-Density Lipoprotein Particle Size, and Apolipoprotein A-I: Significance for Cardiovascular Risk: The IDEAL and EPIC-Norfolk Studies

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Objectives

This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary artery disease (CAD), with a focus on the effect of very high values of these parameters.

Background

High plasma levels of HDL-C and apoA-I are inversely related to the risk of CAD. However, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed.

Methods

We conducted a post-hoc analysis of 2 prospective studies: the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk case-control study, including apparently healthy individuals who did (cases, n = 858) or did not (control patients, n = 1,491) develop CAD during follow-up. In IDEAL, only HDL-C and apoA-I were available; in EPIC-Norfolk, nuclear magnetic resonance spectroscopy-determined HDL particle sizes were also available.

Results

In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies.

Conclusions

When apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This does not hold true for very high levels of apoA-I at fixed levels of HDL-C and apoB. These findings may have important consequences for assessment and treatment of CAD risk.

Abbreviations and Acronyms

ApoA-I
apolipoprotein A-I
ApoB
apolipoprotein B
CAD
coronary artery disease
CETP
cholesteryl ester transfer protein
HDL-C
high-density lipoprotein cholesterol
LDL-C
low-density lipoprotein cholesterol
MCE
major coronary event
MI
myocardial infarction
NMR
nuclear magnetic resonance
OR
odds ratio
RR
relative risk

Cited by (0)

The IDEAL study was sponsored by Pfizer. Pfizer did not provide financial support for the present post-hoc analysis. The EPIC-Norfolk study is supported by program grants from the Medical Research Council (United Kingdom) and Cancer Research UK and receives additional support from the European Union, Stroke Association, British Heart Foundation, United Kingdom Department of Health, Food Standard Agency, and the Wellcome Trust. Some of the lipid and apolipoprotein measurements described in this article were funded by an educational grant from the Future Forum. The funding sources had no role in the study design, conduct, or analysis or in the decision to submit the manuscript for publication. For full author disclosures, please see the end of this paper.